In Study 201/202, all 12 boys on eteplirsen had a significant increase in dystrophin-positive fibers at about 3 years: a 15-fold increase as measured by a panel of independent pathologists as requested by the FDA, and a seven-fold increase (P<0.001 for both) on an analysis done by Jerry Mendell, MD, director of neuromuscular disorders at Nationwide Children's Hospital in Columbus, Ohio, and colleagues.

The children could also put down greater distance on the 6-Minute Walk Test at that time than historical controls (mean difference of 151 meters, P<0.01), Mendell reported at the American Academy of Neurology annual meeting.

Although the drug's accelerated approval was controversial, Mendell said the agent had three characteristics that persuaded the FDA to give it the green light: "It has to be safe, and eteplirsen is impeccable in that regard. It had to show good biochemistry and biomarkers, and good functional outcomes. Eteplirsen reached all of those markers."

The first half of the study (201) enrolled 12 patients -- all boys with DMD over age 7, who were randomized to one of three groups: weekly infusions of either 30 mg/kg or 50 mg/kg, or to placebo.

At week 25, all of the boys rolled over into Study 202, an open-label trial involving weekly infusions.

During that trial, patients had four muscle biopsies done; trialists had initially planned for three, but the FDA required an additional one done at 180 weeks. Mendell said 11 of the 12 patients agreed to a fourth biopsy at that time.

To measure dystrophin production, the researchers used both Western blots and immunofluorescence to quantify the number of positive fibers. The team also conducted an analysis to measure the intensity of dystrophin-positive fibers. Both Mendell's group and the requested pathologists conducted independent assessments.

On Western blot, there was an 11-fold increase in dystrophin-positive fibers at 180 weeks over baseline (P=0.007), and on immunofluorescence, there was a seven-fold increase (P<0.001), Mendell reported. The independent pathologists found a 15-fold increase in dystrophin-positive fibers on immunofluoroscopy (P<0.001).

Both the researchers and the independent pathologists found a twofold increase in the intensity of the dystrophin-positive fibers (P<0.001).

"There's no doubt that dystrophin had been produced," Mendell said.

For the 6-Minute Walk Test, the researchers compared the 12 boys in the study cohort with 13 well-matched historical controls, and found that boys on eteplirsen had a 75-meter advantage at 2 years and a 151-meter advantage at 3 years (P<0.01).

Only 2 of the 12 study patients (17%) lost ambulation during the study, while 46% of historical controls lost ambulation at 3 years and 85% lost ambulation by 4 years, he reported.

"I want to emphasize that this is not a cure for the disease, but it's a change in the rate of decline," Mendell said.

There were no significant treatment-related adverse events, and most were related to the infusions or biopsy, he said. There were no renal complications or immune responses: "Eteplirsen is very well tolerated and safe."

During his presentation, Mendell played a video of one 15-year-old boy in the study who was participating in a charity walk and who was able to run part of the way.

Daniel Kantor, MD, of Florida Atlantic University in Boca Raton, Fla., who was not involved in the study, cautioned about the lack of randomized, controlled data to support the use of eteplirsen, but offered a positive outlook for the drug: "Although the data supporting eteplirsen has gaps -- the use of historical controls and surrogate endpoints -- DMD remains a disease with a desperate need for an effective treatment," Kantor told MedPage Today. "Given the unmet need and with appropriate tracking, it is reasonable to use to offer hope for our patients."

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